核变形性通过增加微管体依赖的DNA断裂流动性,增加了BRCA1缺乏细胞中的PARPi敏感性
Elena Faustini1, Angela Dello Stritto1, Andrea Panza1
1Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
Nature communications
|June 17, 2025
概括
微管和核包膜浸增强了BRCA1缺乏细胞治疗PARP抑制剂 (PARPi) 的DNA双链断裂 (DSB) 流动性. 增加核外的变形性可能会提高PARPi癌症治疗的疗效.
科学领域:
- 细胞生物学 细胞生物学
- 遗传学 是一个遗传学.
- 癌症研究 癌症研究
背景情况:
- 微管和SUN1/2蛋白质在辐射后促进DNA双链断裂 (DSB) 的移动性.
- 微管和核结构在DSB修复中的作用,特别是在BRCA1缺乏细胞中使用Poly (ADP-ribose) 聚合酶抑制剂 (PARPi) 治疗后,仍然不清楚.
研究的目的:
- 为了研究微管体依赖的DSB流动性和在PARPi治疗后BRCA1缺乏细胞的核结构变化之间的关联.
- 确定核外 (NE) 变形是否影响DSB修复,染色体异常和PARPi细胞毒性.
主要方法:
- 使用了BRCA1缺陷细胞模型.
- 用PARPi处理的细胞.
- 通过LMNA删除或脂蛋白合成抑制诱导的核包膜侵蚀.
- 评估了DSB的移动性,染色体异常和细胞毒性.
主要成果:
- 在PARPi处理的BRCA1缺陷细胞中,微管体依赖的DSB流动性与核包膜侵蚀相关.
- 增加的NE侵入 (通过LMNA删除或脂合成抑制) 增强DSB的移动性,染色体异常和PARPi细胞毒性.
- 这些发现确定了NE结构和DSB维修之间的联系.
结论:
- 核膜变形性是调节BRCA1缺乏细胞中DNA双链断裂修复和对PARPi的反应的关键因素.
- 准NE变形性是一个潜在的治疗策略,可以提高BRCA1缺陷癌症中PARPi的疗效.
相关概念视频
Long-patch Base Excision Repair
7.2K
Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
7.2K
Restarting Stalled Replication Forks
5.9K
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
5.9K
Fixing Double-strand Breaks
12.9K
The double-stranded structure of DNA has two major advantages. First, it serves as a safe repository of genetic information where one strand serves as the back-up in case the other strand is damaged. Second, the double-helical structure can be wrapped around proteins called histones to form nucleosomes, which can then be tightly wound to form chromosomes. This way, DNA chains up to 2 inches long can be contained within microscopic structures in a cell. A double-stranded break not only damages...
12.9K
DNA Damage can Stall the Cell Cycle
9.3K
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.3K
Nucleotide Excision Repair
3.9K
DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
3.9K
Homologous Recombination
52.8K
The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
52.8K


